FD/MAS: To better define the best surgical care of craniofacial FD, we examined the surgical indications and risk factors for recurrence in the NIH cohort. 133 subjects with craniofacial FD were evaluated. Radiographic studies, operative reports, and clinical records were reviewed. 36 subjects underwent 103 craniofacial procedures (mean, 2.8 operations per subject), with 13.5 10.5-year follow-up (range, 0 to 39 y). The most common indication was craniofacial deformity (n = 61 operations), including 36 initial operations (59%) and 26 reoperations (41%). Mean time to reoperation was 3.4 3.2 y (range, 0.3 to 13.3 y). Regrowth occurred after 42 operations (68%), and was more frequent after operations in subjects with MAS with growth hormone (GH) excess (22 of 25 operations, 88%) than without GH excess (15 of 36 operations, 58%); p = 0.02. Of 11 subjects with GH excess, nine (82%) were undiagnosed at the time of their initial operation. Regrowth was more frequent after debulking procedures 31 of 38 (82%) than after more aggressive reconstructions (9 of 20, 45%; p = 0.007). 11 subjects underwent treatment for aneurysmal bone cysts, with recurrence in one subject. 11 subjects underwent biopsies without complications or regrowth. We concluded that regrowth and reoperation are common, particularly after debulking procedures. Outcomes are favorable for aneurysmal bone cysts and biopsies. In MAS GH excess is a risk factor for regrowth, and may be underdiagnosed. Surgeons should be aware of appropriate screening for endocrinopathies in FD. These findings highlight the importance of a multidisciplinary approach to craniofacial FD, and individualized care with long-term follow-up. Osteonecrosis of the jaw (ONJ) is an established side effect of bisphosphonates. Although frequently prescribed for patients with FD, there are no reports of ONJ in the literature. This has led some to conclude that patients with FD are at low risk for the development of bisphosphonate-related ONJ. We reviewed the NIH cohort to determine the prevalence and risk factors for the development of ONJ in patients with FD. Of the 76 patients with FD in the NIH cohort who were treated with bisphosphonates, 4 developed ONJ (5.4%). 3 patients developed ONJ in areas of FD-affected bone and 1 in an area of normal bone. All 4 patients had features known to be associated with ONJ in the general population, including long-term high-dose intravenous bisphosphonate treatment, periodontal and endodontic infections, and dentoalveolar surgical procedures. These cases establish ONJ as a potential complication of bisphosphonate treatment in patients with FD. The presence of established risk factors for ONJ in this group of patients with FD suggests that high-risk patients could be identified before the development of ONJ. Clinicians should use caution in prescribing bisphosphonates to patients with FD and should do so only for established indications. We had previously demonstrated that letrozole is a potentially effective treatment of girls with MAS-associated precocious puberty. In this study, we evaluated the long-term safety and efficacy of letrozole treatment in large cohort of girls with MAS-associated precocious puberty. We performed a retrospective analysis of the NIH cohort of patients with MAS. Clinical data, including history and physical examination, bone age, and pelvic ultrasounds, were reviewed on 28 letrozole-treated girls. Adult height was reviewed for 42 historical controls. Outcomes included rate of skeletal maturation, growth velocity, predicted adult height and adult height. 28 girls received letrozole. Treatment duration was 4.1+/- 2.6 years (mean+/-1 s.d.) (range: 0.5-10.9) and mean follow-up was 6.0+/-3.3 years (range: 0.5-15.0), for a total of 135.9 person-years of follow-up. Letrozole treatment was highly effective at decreasing the rate of skeletal maturation, with a decline in change in bone age over change in chronological age (BA/CA) from 1.7 (IQR: 2.3) to 0.5 (IQR: 0.4) (P<0.0001), and growth velocity Z-scores, which declined from 2.2+/-2.3 to -0.6+/-1.6 (P=0.0004). Predicted adult height Z-scores increased significantly from -2.9+/-3.2 to -0.8+/-1.5 for subjects on treatment (P=0.004). 4 subjects who completed treatment reached adult height Z-scores ranging from -1.5 to 1.7 (median: -0.6), which were increased in comparison with untreated historical controls (P=0.02). There was no change in uterine size or ovarian volumes, and no adverse events over the treatment period. In this study with the longest follow-up to date, letrozole treatment resulted in sustained beneficial effects on skeletal maturation, growth velocity and predicted adult height. Mineral Homeostasis: We evaluated the effects of temperature, handling, length of storage, and freeze-thaw cycles on FGF23 from our cohorts of patients with FGF23 excess. Serum and plasma FGF23 were measured using three commercially-available ELISA assays, two measuring iFGF23 and one measuring cFGF23. Samples from subjects with known FGF23 disorders were stored at 4, 22, and 37 C and analyzed at different intervals up to 48 hours. A subset of samples underwent repeated freeze-thaw cycles, and samples frozen at -80 C for up to 60 months were reanalyzed. The effect of adding a furin convertase inhibitor on FGF23 degradation was investigated. Plasma FGF23 levels were stable when stored at 4 and 22 C for 48 h. Both plasma and serum FGF23 levels demonstrated relative stability after 5 freeze-thaw cycles. Long-term storage at -80 C for 60 months induced variability in FGF23 levels. The addition of a furin inhibitor did not affect FGF23 degradation. Intact FGF23 levels showed good correlation only at the upper end of the assay range when comparing the two assays. These data we determined that the sample type, handling, and choice of assay are factors that affect FGF23 levels and should be considered. Octreotide has been proposed as a potential treatment for TIO due to the presence of somatostatin receptors (SSTR) on phosphaturic mesenchymal tumors (PMTs); however, the role of somatostatin signaling in PMTs and the efficacy of treatment of TIOs with somatostatin analogues is not clear. In an effort to evaluate the efficacy of octreotide therapy in TIO, five subjects with TIO were treated with octreotide for 3 days. Blood intact FGF23, phosphate, and 1,25(OH)2 D3, and tubular reabsorption of phosphate (TRP) were measured at frequent time points during treatment. Octreotide's effects were assessed by comparing group means of the biochemical parameters at each time-point to mean baseline values. There were no significant changes in blood phosphate, FGF23, 1,25(OH)2 D3, or TRP during octreotide treatment, consistent with a lack of efficacy of octreotide in treating TIO. To investigate the ability 68Ga-DOTATATE PET/computed tomography (CT) for tumor localization in TIO, we performed a single-center prospective study of patients with TIO. Eleven subjects (six females, five males) with TIO were included and underwent 68Ga-DOTATATE PET/CT in addition to 111In-pentetreotide single-photon emission CT (Octreoscan- SPECT/CT) and fluorodeoxyglucose-PET/CT (18F FDG-PET/CT) scanning. The primary outcome was localization of PMTs. The tumor was successfully localized in 6/11 (54.5%) subjects (one was metastatic). The tumor was identified by 68Ga-DOTATATE in all six cases. Both Octreoscan-SPECT/CT and 18F FDG-PET each identified the tumor in 4/6. In no cases was 68Ga-DOTATATE the only imaging study to identify the tumor. In this first prospective study comparing 68Ga-DOTATATE PET/CT to Octreoscan-SPECT/CT and 18F FDG-PET in TIO localization, 68Ga-DOTATATE PET/CT demonstrated the greatest sensitivity and specificity, suggesting that it may be the best single study for localization of PMTs in TIO.